The present invention relates to novel enkephalinase B inhibitors.
Following the discovering of morphine receptors in vivo, a search was made for endogenous morphine-like substances, and the pentapeptides methionine-enkephalin (Tyr-Gly-Gly-Phe-Met) and leucine-enkephalin (Tyr-Gly-Gly-Phe-Leu) were found in mammalian brain by Hughes et al. (Nature, 258, 577 (1975)). Various other endogenous opioid peptides were subsequently found and it became apparent that these other peptides necessarily have a methionine-enkephalin or leucine-enkephalin structure at their N-terminal region.
Enkephalins (Met-enkephalin and Leu-enkephalin) are generally short-lived in vivo, being rapidly degraded into active derivatives, so their potential value as pharmaceuticals is limited because their analgesic function cannot last long after administration. If suitable enzyme inhibitors could be found to suppress the degradation of enkephalins in vivo, their biological activity could be maintained, making them potentially useful as analgesics.
The degradation system in the brain includes aminopeptides which exist in the soluble fraction and the brain membrane, as well as enkephalinase A, enkephalinase B and angiotensin-converting enzymes which exist in the membrane. Aminopeptidases cleave the Tyr-Gly bond of enkephalins and release Tyr, whereas enkephalinase A and angiotensin-converting enzymes cleave the Gly-Phe bond and release Tyr-Gly-Gly. Aminopeptidase inhibitors are known, such as puromycin (Proc. Natl. Acad. Sci., U.S.A. 69, 624 (1972)), bestatin (J. Antibiotics, 29, 97 (1976)), amastatin (J. Antibiotics, 31, 636 (1978)) and alphamenine (J. Antibiotics, 36, 1572, 1576 (1983)). Enkephalinase A inhibitors are also known, such as thiorphan (Nature, 288, 286 (1980)) and phosphoramidon (Life Science, 29, 2593 (1981)). Enkephalinase A inhibitors are also described in French patent specification Nos. 2 480 747 and 2 518 088 (corresponding to Japanese laid-open patent application "kokai" No. 58-150547).
On the other hand, to the best of our present knowledge, the action of enkephalinase B has not previously been investigated in detail, and no effective inhibitors for it have been described hitherto.